Most research institutions are essentially collections of independent laboratories, each run by principal investigators who head a team of trainees. This scheme has ancient roots and a track record of success. But it is not the only way to do science. Indeed, for much of modern biomedical research, the traditional organization has become limiting.
A different model is thriving at the Broad Institute of MIT and Harvard in Cambridge, Massachusetts, where I work. In the 1990s, the Whitehead Institute for Biomedical Research, a self-governing organization in Cambridge affiliated with the Massachusetts Institute of Technology (MIT), became the academic leader in the Human Genome Project. This meant inventing and applying methods to generate highly accurate DNA sequences, characterize errors precisely and analyse the outpouring of data. These project types do not fit neatly into individual doctoral theses. Hence, the institute created a central role for staff scientists — individuals charged with accomplishing large, creative and ambitious projects, including inventing the means to do so. These non-faculty scientists work alongside faculty members and their teams in collaborative groups.
When leaders from the Whitehead helped to launch the Broad Institute in 2004, they continued this model. Today, our work at the Broad would be unthinkable without professional staff scientists — biologists, chemists, data scientists, statisticians and engineers. These researchers are not pursuing a tenured academic post and do not supervise graduate students, but do cooperate on and lead projects that could not be accomplished by a single academic laboratory.
Physics long ago saw the need to expand into different organizational models. The Manhattan Project, which during the Second World War harnessed nuclear energy for the atomic bomb, was not powered by graduate students. Europe's particle-physics laboratory, CERN, does not operate as atomized labs with each investigator pursuing his or her own questions. And the Jet Propulsion Laboratory at the California Institute of Technology in Pasadena relies on professional scientists to get spacecraft to Mars.
In biology, many institutes in addition to the Broad are experimenting with new organizational principles. The Mechanobiology Institute in Singapore pushes its scientists to use tools from other disciplines by discouraging individual laboratories from owning expensive equipment unless it is shared by all. The Howard Hughes Medical Institute's Janelia Research Campus in Ashburn, Virginia, the Salk Institute of Biological Sciences in La Jolla, California, and the Allen Institute for Brain Science in Seattle, Washington, effectively mix the work of faculty members and staff scientists. Disease-advocacy organizations, such as the ALS Therapy Development Institute in Cambridge, do their own research without any faculty members at all.
Each of these institutes has a unique mandate, and many are fortunate in having deep resources. They also had to be willing to break with tradition and overcome cultural barriers.
At famed research facilities of yore, such as Bell Labs and IBM Laboratories, the title 'staff scientist' was a badge of honour. Yet to some biologists the term suggests a permanent postdoc or senior technician — someone with no opportunities for advancement who works solely in a supervisor's laboratory, or who runs a core facility providing straightforward services. That characterization sells short the potential of professional scientists.
The approximately 430 staff scientists at the Broad Institute develop cutting-edge computational methods, invent and incorporate new processes into research pipelines and pilot and optimize methodologies. They also transform initial hits from drug screens into promising chemical compounds and advance techniques to analyse huge data sets. In summary, they chart the path to answering complex scientific questions.
Although the work of staff scientists at the Broad Institute is sometimes covered by charging fees to its other labs, our faculty members would never just drop samples off with a billing code and wait for data to be delivered. Instead, they sit down with staff scientists to discuss whether there is an interesting collaboration to be had and to seek advice on project design. Indeed, staff scientists often initiate collaborations.
Naturally, tensions still arise. They can play out in many ways, from concerns over how fees are structured, to questions about authorship. Resolving these requires effort, and it is a task that will never definitively be finished.
In my view, however, the staff-scientist model is a win for all involved. Complex scientific projects advance more surely and swiftly, and faculty members can address questions that would otherwise be out of reach. This model empowers non-faculty scientists to make independent, creative contributions, such as pioneering new algorithms or advancing technologies. There is still much to do, however. We are working to ensure that staff scientists can continue to advance their careers, mentor others and help to guide the scientific direction of the institute.
As the traditional barriers break down, science benefits. Technologies that originate in a faculty member's lab sometimes attract more collaborations than one laboratory could sustain. Platforms run by staff scientists can incorporate, disseminate and advance these technologies to capture more of their potential. For example, the Broad Institute's Genetic Perturbation Platform, run by physical chemist David Root, has honed high-throughput methods for RNA interference and CRISPR screens so that they can be used across the genome in diverse biological contexts. Staff scientists make the faculty more productive through expert support, creativity, added capacity and even mentoring in such matters as the best use of new technologies. The reverse is also true: faculty members help staff scientists to gain impact.
Our staff scientists regularly win scientific prizes and are invited to give keynote lectures. They apply for grants as both collaborators and independent investigators, and publish regularly. Since 2011, staff scientists have led 36% of all the federal grants awarded for research projects at the Broad Institute (see ‘Staff-led grants’). One of our staff scientists, genomicist Stacey Gabriel, topped Thomson Reuters' citation analysis of the World's Most Influential Scientific Minds in 2016. She co-authored 25 of the most highly cited papers in 2015 — a fact that illustrates both how collaborative the Broad is and how central genome-analysis technologies are to answering key biological questions.
At the Broad Institute's Stanley Center for Psychiatric Research, which I direct, staff scientists built and operate HAIL, a powerful open-source tool for analysis of massive genetics data sets. By decreasing computational time, HAIL has made many tasks 10 times faster, and some 100 times faster. Staff scientist Joshua Levin has developed and perfected RNA-sequencing methods used by many colleagues to analyse models of autism spectrum disorders and much else. Nick Patterson, a mathematician and computational biologist at the Stanley Center, began his career by cracking codes for the British government during the cold war. Today, he uses DNA to trace past migrations of entire civilizations, helps to solve difficult computational problems and is a highly valued support for many biologists.
Why haven't more research institutions expanded the roles of staff scientists? One reason is that they can be hard to pay for, especially by conventional means. Some funding agencies look askance at supporting this class of professionals; after all, graduate students and postdocs are paid much less. In my years leading the US National Institute of Mental Health, I encountered people in funding bodies across the world who saw a rising ratio of staff to faculty members or of staff to students as evidence of fat in the system.
That said, there are signs of flexibility. In 2015, the US National Cancer Institute began awarding 'research specialist' grants — a limited, tentative effort designed in part to provide opportunities for staff scientists. Sceptical funders should remember that trainees often take years to become productive. More importantly, institutions' misuse of graduates and postdocs as cheap labour is coming under increasing criticism (see, for example, et al. Proc. Natl Acad. Sci. USA 111, 5773–5777; 2014).
Faculty resistance is also a factor. I served as Harvard University's provost (or chief academic officer) for a decade. Several years in, I launched discussions aimed at expanding roles for staff scientists. Several faculty members worried openly about competition for space and other scarce resources, especially if staff scientists were awarded grants but had no teaching responsibilities. Many recoiled from any trappings of corporatism or from changes that felt like an encroachment on their decision-making. Some were explicitly concerned about a loss of access and control, and were not aware of the degree to which staff scientists' technological expertise and cross-disciplinary training could help to answer their research questions.
Institutional leaders can mitigate these concerns by ensuring that staff positions match the shared goals of the faculty — for scientific output, education and training. They must explain how staff-scientist positions create synergies rather than silos. Above all, hiring plans must be developed collaboratively with faculty members, not by administrators alone.
The Broad Institute attracts world-class scientists, as both faculty members and staff. Its appeal has much to do with how staff scientists enable access to advanced technology, and a collaborative culture that makes possible large-scale projects rarely found in academia. The Broad is unusual — all faculty members also have appointments at Harvard University, MIT or Harvard-affiliated hospitals. The institute has also benefited from generous philanthropy from individuals and foundations that share our values and believe in our scientific mission.
Although traditional academic labs have been and continue to be very productive, research institutions should look critically and creatively at their staffing. Creating a structure like that of the Broad Institute would be challenging in a conventional university. Still, I believe any institution that is near an academic health centre or that has significant needs for advanced technology could benefit from and sustain the careers of staff scientists. If adopted judiciously, these positions would enable institutions to take on projects of unprecedented scope and scale. It would also create a much-needed set of highly rewarding jobs for the rising crop of talented researchers, particularly people who love science and technology but who do not want to pursue increasingly scarce faculty positions.
A scientific organization should be moulded to the needs of science, rather than constrained by organizational traditions.

Researchers from the Mechanobiology Institute, Singapore (MBI) at the National University of Singapore have described, for the first time, how plastin, an actin-bundling protein, acts as a molecular rivet, providing global connectivity to the cortex underlying the plasma membrane of embryonic cells to facilitate polarisation and cell division. The work was published in The Journal of Cell Biology on 11 April 2017.
All multicellular organisms begin their life when a sperm cell fuses with an oocyte. The newly fertilised zygote must then undergo countless rounds of cell division as it forms an embryo. Some divisions are symmetric and generate two identical daughter cells in a process known as cytokinesis. Others are asymmetric, and result in unequal daughter cells that differentiate into distinct cell types with specialised functions. Before asymmetric division, these cells undergo a process known as polarisation, where the top or front of the cell contains a different set of protein-based structures and machines to the bottom or back of the cell.
Both cytokinesis and polarisation are driven by a contractile component of the cell called the cortex. This thin layer is located inside the cell, immediately adjacent to the plasma membrane and is primarily composed of actin filaments (F-actin), which are cable-like structures that are dynamically assembled and disassembled, and maintain cell shape. The cortex also contains the motor protein non-muscle myosin II, which confers contractility to the network, and other actin-binding proteins such those that bundle filaments together or facilitate the assembly of new filaments. Despite the structural arrangement of the cortex being well established, it was unclear how all of these proteins work together in a living organism to produce higher order actin-based structures, and transmit mechanical force during crucial developmental processes.
To investigate these questions, a team of interdisciplinary scientists from MBI, A*STAR's Institute of Molecular and Cell Biology, and the European Molecular Biology Laboratory, examined the cortex in a developing organism, specifically, Caenorhabditis elegans (C. elegans), which is a 1mm long transparent nematode worm. What became apparent from the investigation, which was led by Assistant Professor Ronen Zaidel-Bar, was the important role of an actin-binding protein called plastin (a.k.a. fimbrin) in early C. elegans development.
Plastin binds to actin filaments to facilitate their bundling and strengthen the actin filament network so that it can withstand the forces generated during filament contraction, and also those applied to the cortex from external stimuli. By functioning as a molecular rivet, plastin enabled the cell cortex to function efficiently, thereby facilitating polarisation and cytokinesis. Using microscopy, genetic and computer modelling approaches, the researchers examined the cell cortex during the earliest stages of C. elegans development, with a particular focus on plastin. Although previous efforts had identified plastin within the cortex, none had revealed its full importance in the development of an embryo.
To begin the investigations, MBI PhD candidate Mr Ding Wei Yung examined zygotes from a mutant strain of C. elegans where the function of plastin had been lost. In these zygotes, both polarisation and cytokinesis were disrupted to the point that they either did not occur, or were significantly delayed. With the ability to observe how C. elegans formed with plastin mutated, the researchers turned their attention to examining contractility within the cortex, during C. elegans development.
To do this, the researchers examined the organisation and dynamics of non-muscle myosin II at the cortex during polarisation. In normal zygotes, the myosin motor proteins will accumulate into large clusters that generate large contractile forces. However, when plastin function was lost, the researchers noted that the myosin did not accumulate in clusters as it does in normal cells. This meant that the contractions generated were much weaker compared to normal cells. Ultimately, the loss of strong, coordinated cortical contractions in the plastin mutant worm embryo resulted in defective polarisation. This was evident from the disrupted separation of two proteins that would otherwise accumulate at either end of the cells as they underwent polarisation.
The authors then extended their investigation beyond polarisation and looked at the role of plastin in cytokinesis. In healthy zygotes, actin filaments, together with non-muscle myosin II, will accumulate in the middle of the dividing cells. From there they effectively pull the membrane inwards so that opposing sides of the cell meet and fuse, thereby creating two cells. This did not occur at the same rate in cells containing mutated plastin, and it was determined that plastin facilitates the accumulation of the proteins in the correct position.
To better understand why plastin-mediated cross-linking of actomyosin filaments had these effects on cell polarisation and cytokinesis, the team turned to mathematical modeling. Specifically, they tested whether increased connectivity between plastin and actomyosin alone is sufficient to drive long-range cortical contractility. These simulations revealed an optimal level of plastin crosslinking required to facilitate these processes, and indicated that too little or too much cross-linking will result in an F-actin network that is either too disconnected or too stiff. In both cases, the end result is weakened contractility. To confirm that this was true in living organisms, the team increased the levels of plastin in the healthy C. elegans zygotes, and found that indeed, having too much plastin substantially slowed down cytokinesis.
Embryogenesis requires robust force generation and transmission that drives critical cellular processes such as polarisation and cytokinesis. The findings presented in this work elucidate a role for plastin as a molecular rivet to facilitate robust polarisation and timely cytokinesis. These discoveries further demonstrate the importance of the high-order organisation of the actomyosin cytoskeleton and the role of actin binding proteins, such as plastin, in regulating its function.

Researchers from the Mechanobiology Institute, Singapore (MBI) at the National University of Singapore have described, for the first time, how plastin, an actin-bundling protein, acts as a molecular rivet, providing global connectivity to the cortex underlying the plasma membrane of embryonic cells to facilitate polarisation and cell division. The work was published in The Journal of Cell Biology on 11 April 2017.
All multicellular organisms begin their life when a sperm cell fuses with an oocyte. The newly fertilised zygote must then undergo countless rounds of cell division as it forms an embryo. Some divisions are symmetric and generate two identical daughter cells in a process known as cytokinesis. Others are asymmetric, and result in unequal daughter cells that differentiate into distinct cell types with specialised functions. Before asymmetric division, these cells undergo a process known as polarisation, where the top or front of the cell contains a different set of protein-based structures and machines to the bottom or back of the cell.
Both cytokinesis and polarisation are driven by a contractile component of the cell called the cortex. This thin layer is located inside the cell, immediately adjacent to the plasma membrane and is primarily composed of actin filaments (F-actin), which are cable-like structures that are dynamically assembled and disassembled, and maintain cell shape. The cortex also contains the motor protein non-muscle myosin II, which confers contractility to the network, and other actin-binding proteins such those that bundle filaments together or facilitate the assembly of new filaments. Despite the structural arrangement of the cortex being well established, it was unclear how all of these proteins work together in a living organism to produce higher order actin-based structures, and transmit mechanical force during crucial developmental processes.
To investigate these questions, a team of interdisciplinary scientists from MBI, A*STAR's Institute of Molecular and Cell Biology, and the European Molecular Biology Laboratory, examined the cortex in a developing organism, specifically, Caenorhabditis elegans (C. elegans), which is a 1mm long transparent nematode worm. What became apparent from the investigation, which was led by Assistant Professor Ronen Zaidel-Bar, was the important role of an actin-binding protein called plastin (a.k.a. fimbrin) in early C. elegans development.
Plastin binds to actin filaments to facilitate their bundling and strengthen the actin filament network so that it can withstand the forces generated during filament contraction, and also those applied to the cortex from external stimuli. By functioning as a molecular rivet, plastin enabled the cell cortex to function efficiently, thereby facilitating polarisation and cytokinesis. Using microscopy, genetic and computer modelling approaches, the researchers examined the cell cortex during the earliest stages of C. elegans development, with a particular focus on plastin. Although previous efforts had identified plastin within the cortex, none had revealed its full importance in the development of an embryo.
To begin the investigations, MBI PhD candidate Mr Ding Wei Yung examined zygotes from a mutant strain of C. elegans where the function of plastin had been lost. In these zygotes, both polarisation and cytokinesis were disrupted to the point that they either did not occur, or were significantly delayed. With the ability to observe how C. elegans formed with plastin mutated, the researchers turned their attention to examining contractility within the cortex, during C. elegans development.
To do this, the researchers examined the organisation and dynamics of non-muscle myosin II at the cortex during polarisation. In normal zygotes, the myosin motor proteins will accumulate into large clusters that generate large contractile forces. However, when plastin function was lost, the researchers noted that the myosin did not accumulate in clusters as it does in normal cells. This meant that the contractions generated were much weaker compared to normal cells. Ultimately, the loss of strong, coordinated cortical contractions in the plastin mutant worm embryo resulted in defective polarisation. This was evident from the disrupted separation of two proteins that would otherwise accumulate at either end of the cells as they underwent polarisation.
The authors then extended their investigation beyond polarisation and looked at the role of plastin in cytokinesis. In healthy zygotes, actin filaments, together with non-muscle myosin II, will accumulate in the middle of the dividing cells. From there they effectively pull the membrane inwards so that opposing sides of the cell meet and fuse, thereby creating two cells. This did not occur at the same rate in cells containing mutated plastin, and it was determined that plastin facilitates the accumulation of the proteins in the correct position.
To better understand why plastin-mediated cross-linking of actomyosin filaments had these effects on cell polarisation and cytokinesis, the team turned to mathematical modeling. Specifically, they tested whether increased connectivity between plastin and actomyosin alone is sufficient to drive long-range cortical contractility. These simulations revealed an optimal level of plastin crosslinking required to facilitate these processes, and indicated that too little or too much cross-linking will result in an F-actin network that is either too disconnected or too stiff. In both cases, the end result is weakened contractility. To confirm that this was true in living organisms, the team increased the levels of plastin in the healthy C. elegans zygotes, and found that indeed, having too much plastin substantially slowed down cytokinesis.
Embryogenesis requires robust force generation and transmission that drives critical cellular processes such as polarisation and cytokinesis. The findings presented in this work elucidate a role for plastin as a molecular rivet to facilitate robust polarisation and timely cytokinesis. These discoveries further demonstrate the importance of the high-order organisation of the actomyosin cytoskeleton and the role of actin binding proteins, such as plastin, in regulating its function.

Researchers at the Mechanobiology Institute (MBI) at the National University of Singapore (NUS) have identified a role of receptor tyrosine kinases in the regulation of the cellular mechanosensory machinery, which has relevance for understanding the basis of cancerous growth and developmental abnormalities. The work was published in Nano Letters in August 2016.

Scientists from the Mechanobiology Institute, Singapore (MBI) at the National University of Singapore have discovered the universal building blocks that cells use to form initial connections with the surrounding environment. These early adhesions have a consistent size of 100 nanometres, are made up of a cluster of around 50 integrin proteins and are the same even when the surrounding surface is hard or soft. Deciphering the universal nature of adhesion formation may reveal how tumour cells sense and migrate on surfaces of different rigidity, which is a hallmark of metastasis, the devastating ability of cancer to spread throughout the body.

Scientists from the Mechanobiology Institute (MBI) at the National University of Singapore (NUS) have discovered a new mechanism of cell boundary elongation. Elongation and contraction of the cell boundary is essential for directing changes in cell shape, which is required for the correct development of tissues and organs. The study was published in Current Biology on 11 August 2016.

Scientists from the Mechanobiology Institute, Singapore (MBI) at the National University of Singapore (NUS) have discovered that cadherin clusters, which are well known for forming junctions between cells, also play a role in stabilising the cell cortex. The study was published in the scientific journal Current Biology on 15 December 2016.
Scientists from the Mechanobiology Institute, Singapore (MBI) at the National University of Singapore (NUS) have discovered that cadherin clusters, which are well known for forming junctions ...
Scientists have discovered that cadherin clusters, which are well known for forming junctions between cells, also play a role in stabilizing the cell cortex.
Scientists from the Mechanobiology Institute, Singapore at the National University of Singapore have discovered that cadherin clusters, which are well known for forming junctions between cells, ...

An international collaboration between scientists from the Mechanobiology Institute (MBI) at the National University of Singapore (NUS) and the Institut Jacques Monod and Université Paris Diderot, France, has revealed how epithelial cell extrusion is regulated by cell density. The study was published in the scientific journal Current Biology on 5 October 2016.
The external and internal surfaces of the body are covered by a layer of cells known as epithelial cell sheets. The classic example of an epithelial cell sheet is skin, but epithelial layers also line internal cavities such as blood vessels, the stomach, and the mouth. The primary role of these cell sheets is to provide a protective barrier against physical damage and infection. In order to perform these functions, the integrity of the epithelial cell sheet must be maintained by balancing cell renewal and removal. For example, the layer of cells lining the intestine is renewed every five days. Deteriorating, damaged, or unnecessary cells are targeted for elimination by apoptosis - the process of programmed cell death - allowing them to be eliminated without causing damage to the neighboring healthy cells, as would occur during inflammation.
Removal of these apoptotic cells from the epithelial cell sheet to maintain an intact barrier layer takes place by the process of cell extrusion. To date, studies have shown that epithelial cell extrusion occurs via formation of a contractile ring made up of protein based cables and motors in the cells surrounding the cell targeted for extrusion. The contractile ring tightens around the base of the extruding cell, pushing it out of the epithelial sheet and bringing the surrounding cells together. Although this 'purse-string' mechanism of contraction is commonly seen in epithelial cell sheets, many of these observations have been based on the assumption that the epithelial layer is a collection of individual cells. However, in reality, these multi-cellular sheets are highly complex structures, with large variations in cell dynamics and cell density.
In order to account for this level of complexity, an interdisciplinary team of biologists, engineers, and biophysicists was assembled by Professor Benoit Ladoux from MBI and Institut Jacques Monod, and Assistant Professor Yusuke Toyama from MBI. The scientists used microfabrication to create circular micro-patterns surfaces that enabled control of the growth and density of epithelial cell sheets. By observing cell extrusion events in cell sheets grown on these patterns, with time-lapse and traction-force microscopy, they discovered that cell density led to two distinct modes of cell extrusion. At a low cell density, the cells in a tissue are dynamic and mobile. As these cells are moving freely, occasionally cell density becomes high in a small patch in the tissue. Cells at this dense region undergo apoptosis, and the cells surrounding the apoptotic cell selected for extrusion collectively crawl towards the targeted cell, and extend large, flat protrusions called lamellipodia underneath it. This action levers the apoptotic cell out of the sheet, causing its extrusion. However, at high density, cells are too tightly packed to move, preventing collective cell migration and lamellipodia-based extrusion. Under these conditions, the cells surrounding the apoptotic cell form a contractile ring, and use purse-string contraction to squeeze out and extrude the cell.
This study revealed, for the first time, that two distinct mechanisms exist to expel apoptotic cells from epithelial cell sheets. Selection between cell extrusion mechanisms is defined by cell density - cell crawling and lamellipodia extension is the predominant mechanism at low density, but purse-string contraction is favoured at high density. The existence of these complementary mechanisms could be important for ensuring the removal of unnecessary cells (e.g. apoptotic cells) in different circumstances to maintain the integrity of the epithelial cell sheet.

Intracellular adherens junctions are initiated by interactions between extracellular domains of membrane-bound cadherins (shown in blue) on adjacent cells. On the intracellular side, the cadherins are linked to the actin cytoskeleton via a cytoplasmic plaque, which is chiefly constituted by catenin proteins: beta-catenins (yellow) and alpha-catenins (purple). The plaque also contains another prominent protein called vinculin (green) that primarily responds to mechanical and biochemical signals by extending in length, and in doing so, couples the cadherin-catenin complexes to the actin cytoskeleton (red). Credit: National University of Singapore The development of super resolution microscopy has revolutionised how scientists view and understand the inner workings of the cell. Just as advances in satellite camera technology gave rise to highly detailed maps of the world, so too has super-resolution microscopy allowed researchers to build detailed maps of individual cells. Such is the detail, that not only is the location of individual protein-based machines achievable, but these machines can be broken down into their parts, and the position and orientation of these parts, mapped out as well.
In the human body, cells rarely function in isolation. Instead they exist as part of multicellular communities that make up tissues and organs. To ensure the tissue functions correctly, individual cells must remain in physical contact with their surrounding cells. When cells are unable to maintain this contact, devastating diseases may arise, cancer being one of the most dreaded examples.
Cell-cell adhesion sites are found at specific regions of the cell periphery. Although many of the protein parts that make up these adhesion sites were known, scientists had yet to determine how each part fit together to make the overall machine. This was because the building blocks of these machines were both far too small for traditional light microscopes, and far too diverse for electron microscopes.
One of the main protein parts in these machines are the 'cadherin' proteins. The cadherin of one cell extends outside the cell, and interact with cadherin of another cell. On the inside of the cell, cadherin binds to 'adaptor' proteins, which essentially connect the cadherin to a network of protein filaments known as the cytoskeleton. By forging these robust links, cadherin adhesions not only connect neighbouring cells but allow cells to coordinate their movements, maintain tissue integrity, and relay a myriad of signals important for proper tissue functions.
With super-resolution microscopy at their disposal, an international research team led by Assistant Professor Pakorn (Tony) Kanchanawong from the Mechanobiology Institute, Singapore (MBI) at the National University of Singapore (NUS) and the Department of Biomedical Engineering at NUS, as well as Dr Cristina Bertocchi, Research Fellow at MBI, has revealed, for the first time, how the cadherin-based cell-cell contacts are organised. At the heart of the study is a 'map' of how the parts are pieced together into a sophisticated nanoscale cell-cell adhesion machine. The study was published online in Nature Cell Biology in December 2016.
Here, the researchers 'mapped' the position and orientation of the protein building blocks of cadherin adhesions. They noted a striking degree of compartmentalisation in the organisation of the protein machinery where components were arranged into multiple layers. The cadherin and the cytoskeleton compartments appeared to be separated by an 'interface layer', which contains vinculin, a stretchable protein which has long been implicated in the cell's ability to sense mechanical force. In this case, Dr Bertocchi observed that vinculin could undergo a dramatic shape-shifting transformation, whereby it would switch from a compact shape to a highly elongated form. This elongated form was sufficient to stretch over a distance of 30 nanometres or more, which was the same distance that cadherin was separated from the cytoskeleton. In a nutshell, vinculin could serve as a bridge to link between the cadherin and actin layers.
Further investigation of this structure highlighted that the shape of vinculin (stretched or compact) was determined by both mechanical tension and biochemical signal inputs. Therefore, the ability of vinculin to selectively engage with a highly dynamic actin cytoskeleton highlights vinculin's role in fine-tuning the mechanical properties of cell-cell contacts in response to varying inputs from the extracellular environment.
The ability to observe, under a microscope, molecular machines such as the cadherin based cell-cell adhesion highlights the power of super resolution microscopy. In this case, the protein parts that make up the cell-cell adhesion have been mapped out, allowing researchers to better understand how cell-cell contacts are formed, maintained, regulated and reinforced to perform vital biological functions.
More information: Cristina Bertocchi et al. Nanoscale architecture of cadherin-based cell adhesions, Nature Cell Biology (2016). DOI: 10.1038/ncb3456

The development of super resolution microscopy has revolutionised how scientists view and understand the inner workings of the cell. Just as advances in satellite camera technology gave rise to highly detailed maps of the world, so too has super-resolution microscopy allowed researchers to build detailed maps of individual cells. Such is the detail, that not only is the location of individual protein-based machines achievable, but these machines can be broken down into their parts, and the position and orientation of these parts, mapped out as well.
In the human body, cells rarely function in isolation. Instead they exist as part of multicellular communities that make up tissues and organs. To ensure the tissue functions correctly, individual cells must remain in physical contact with their surrounding cells. When cells are unable to maintain this contact, devastating diseases may arise, cancer being one of the most dreaded examples.
Cell-cell adhesion sites are found at specific regions of the cell periphery. Although many of the protein parts that make up these adhesion sites were known, scientists had yet to determine how each part fit together to make the overall machine. This was because the building blocks of these machines were both far too small for traditional light microscopes, and far too diverse for electron microscopes.
One of the main protein parts in these machines are the 'cadherin' proteins. The cadherin of one cell extends outside the cell, and interact with cadherin of another cell. On the inside of the cell, cadherin binds to 'adaptor' proteins, which essentially connect the cadherin to a network of protein filaments known as the cytoskeleton. By forging these robust links, cadherin adhesions not only connect neighbouring cells but allow cells to coordinate their movements, maintain tissue integrity, and relay a myriad of signals important for proper tissue functions.
With super-resolution microscopy at their disposal, an international research team led by Assistant Professor Pakorn (Tony) Kanchanawong from the Mechanobiology Institute, Singapore (MBI) at the National University of Singapore (NUS) and the Department of Biomedical Engineering at NUS, as well as Dr Cristina Bertocchi, Research Fellow at MBI, has revealed, for the first time, how the cadherin-based cell-cell contacts are organised. At the heart of the study is a 'map' of how the parts are pieced together into a sophisticated nanoscale cell-cell adhesion machine. The study was published online in Nature Cell Biology in December 2016.
Here, the researchers 'mapped' the position and orientation of the protein building blocks of cadherin adhesions. They noted a striking degree of compartmentalisation in the organisation of the protein machinery where components were arranged into multiple layers. The cadherin and the cytoskeleton compartments appeared to be separated by an 'interface layer', which contains vinculin, a stretchable protein which has long been implicated in the cell's ability to sense mechanical force. In this case, Dr Bertocchi observed that vinculin could undergo a dramatic shape-shifting transformation, whereby it would switch from a compact shape to a highly elongated form. This elongated form was sufficient to stretch over a distance of 30 nanometres or more, which was the same distance that cadherin was separated from the cytoskeleton. In a nutshell, vinculin could serve as a bridge to link between the cadherin and actin layers.
Further investigation of this structure highlighted that the shape of vinculin (stretched or compact) was determined by both mechanical tension and biochemical signal inputs. Therefore, the ability of vinculin to selectively engage with a highly dynamic actin cytoskeleton highlights vinculin's role in fine-tuning the mechanical properties of cell-cell contacts in response to varying inputs from the extracellular environment.
The ability to observe, under a microscope, molecular machines such as the cadherin based cell-cell adhesion highlights the power of super resolution microscopy. In this case, the protein parts that make up the cell-cell adhesion have been mapped out, allowing researchers to better understand how cell-cell contacts are formed, maintained, regulated and re